Automatic or semiautomatic analytical measurement systems are used in the analytical measurement technology, for example, in industrial chemical, biotechnological, pharmaceutical and food technology processes, in the laboratory and in environmental monitoring. These are often designed to pretreat a liquid sample to be analyzed, optionally with the addition of reagents, so that in the presence of an analyte in the sample, a chemical reaction occurs which is detectable by means of physical methods, for example by optical measurements. The analyte content of the sample can be determined, for example, by irradiating the liquid sample with electromagnetic radiation, for example, visible light, from a radiation source, and the reflected radiation is received by a suitable receiver after interaction with the sample. The receiver generates a measurement signal, which depends on the intensity of the radiation received and from which the analyte content of the sample can be derived.
To use analytical method in an automated way, for example, for industrial applications or in the laboratory, it is desirable to provide a suitable automatic or semi-automatic analytical measurement system that performs the necessary analytical methods in an automated way. Such devices are known from, e.g. Published German Applications, DE 10 2009 029305 A1, DE 10 2011 11007011 A1, DE 10 2011 075 762 A1, DE 10 2011 003 615 A1 and DE 10 2011 005 957 A1.
Before the liquid sample to be analyzed is fed to the analyzer, the sample is usually pretreated, for example, by filtering. To this end, automatic or semi-automatic sample preparation devices may be used.
In many cases, the liquid samples to be analyzed are drawn from a process tank, for example, a 1media-carrying pipe or a reaction tank. The reaction tank may be, for example, a bioreactor or a fermenter. Microbial contamination of the tank and the tank contents through the environment must often be prevented for process tanks that are used in bioprocesses in the laboratory or for industrial applications. Therefore, an aseptic sampling is required in such processes. Moreover, chemical processes often need to be protected from chemical recontamination during and after sampling.
The article D. Kuystermans, Mohd A., M. Al-Rubeai, “Automated flow cytometry for monitoring CHO cell cultures”, Methods 56 (3), 2012, pp 358-365, points to the importance of an automated sampling for (quasi-) real-time measurements for better monitoring and control of bioprocesses in a bioreactor, while preventing contamination of the bioreactor. This has a special significance in applications that are subject to the guidelines of the (current) Good Manufacturing Practice (cGMP) This article sets out some commercially available sampling devices for which the applicability is yet to be demonstrated in such cGMP applications.
The published international patent application WO 2010/108091 A2 describes an automated sampling device, which comprises a sampling line, which connects the process tank, from which the sample is to be taken using one or more sample tanks. The liquid sample is transported through the sampling line by a pump that is capable of bidirectional operation. In the process, the pump is meant to flush the liquid sample back into the sample tank from time to time. The sampling line and the sample tank are hermetically sealed. The ventilation ducts opening into the sampling line have a sterile filter, so that no non-sterile substances can get into the sampling line. The entire sampling device should be sterilized.
However, a disadvantage of this sampling device is the potential risk of unwanted, in particular, non-sterile substances entering the process tank due to the option of transporting the drawn liquid back into the process tank. This risk exists, for example, if the sampling device has not been successfully sterilized, or the sampling device has a leak that allows penetration of the non-sterile substances into the sampling line.
The German published patent application DE 10 2006 19 242 A1 discloses a sampling device with a sterilizable sampling valve and a transport system for feeding samples to various analyzers. The sampling valve is designed so as to be fixed on a standardized fermenter adapter of a bioreactor. It has a sample chamber of a defined volume, a front sealing element and a rear sealing element, wherein said front sealing element is opened via a connecting shaft towards the inside of the bioreactor and at the same time, the rear sealing element is sealed against the sample chamber. After closing the valve, the rear sealing element releases the path to an attached transport line.
While the device described in DE 10 2006 19 242 A1 is well suited to applications in industrial processes, its use is problematic in small fermenters in the laboratory, especially in process development, because small fermenters do not generally have suitable standardized fermenter adapters to connect the device to the fermenter. Moreover, likewise the device disclosed by Published International Application WO 2010/108091 A2, this device has no safety mechanism that prevents contamination of the bioreactor in the event that the sampling valve or associated lines are not sterile.
The German published patent application DE 102 46 262 A1 discloses a sampling device for drawing liquid samples from a tank filled with a medium, in particular, a fermenter, via a filter membrane by means of negative pressure, wherein the filter membrane arranged within a sample probe is made of a material acting as a sterile boundary, and wherein a gas feed line and a sample discharge line are arranged on the sterile boundary side of the filter membrane.
For conveying liquid in the discharge line, a negative pressure is applied to it by a pump. The liquid that is so-transferred into the discharge line is transported further by introducing an over-pressurized gas, e.g. compressed air, via the feed line, wherein the gas is passed through a sterile filter before entering the sample probe. A rinsing liquid can be passed via the feed line to the discharge line over the rear boundary of the filter membrane from time to time. The rinsing liquid is transported by the pump. Following the rinsing process, compressed air is led through the feed line to the discharge line over the rear boundary of the filter membrane to remove the rinsing liquid before a liquid sample is taken again from the tank.
During operation of the device disclosed by DE 102 46 262 A1, the rinsing liquid and compressed air reach the tank at the sterile boundary of the filter membrane. The disadvantage here is that the hydrophilic rinsing liquid may well penetrate the equally hydrophilic filter membrane in contrast to the hydrophobic compressed air. By this mass transfer it is possible that the rinsing liquid dilutes the medium, thus influencing the analyte content or the medium is discharged along with the rinsing liquid, which may also affect the bioprocess. Further, in the case of a leak in the membrane, or within the sampling probe containing the membrane, the penetration of non-sterile substances into the tank may also not be excluded here if the rinsing liquid and compressed air are contaminated due to leaks in the pipes, or a failure of the sterile filter.